CN108136214A - Nitrobenzyl derivatives antitumor and anticancer agent - Google Patents

Nitrobenzyl derivatives antitumor and anticancer agent Download PDF

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CN108136214A
CN108136214A CN201680020013.2A CN201680020013A CN108136214A CN 108136214 A CN108136214 A CN 108136214A CN 201680020013 A CN201680020013 A CN 201680020013A CN 108136214 A CN108136214 A CN 108136214A
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compound
alkyl
hydrogen
aryl
group
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CN108136214B (en
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段建新
曹冶宇
蔡晓宏
矫海龙
马靖原
马克·马特西
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Shenzhen Ai Henghao Medical Science & Technology Co Ltd
Molecular Templates Inc
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Abstract

The present invention provides the compound and its intermediary for being suitable as therapeutic agent, the method for the medical composition of these compounds and the cancer for the treatment of cancer patient.Described compound is the aryl ether of aryl benzene being connect with anticancer drug.

Description

Nitrobenzyl derivatives antitumor and anticancer agent
Technical field
The present invention provides the compound for being suitable as therapeutic agent and its intermediary, the medical composition with these compounds And the method for the cancer for the treatment of cancer patient, and be therefore about biology, chemistry and medical domain.
Background technology
Cancer is one of the main reason for the mankind is caused to fall ill and is dead.The treatment of cancer is challenging, because it is difficult to Cancer cell is killed in the case where not damaging or killing normal cell.Being damaged during treatment of cancer or kill normal cell can be Patient's body causes adverse side effect and can limit the amount of the anticancer drug of administration cancer patient.
The member C3 of aldehyde -one reduction enzyme family 1 is by a kind of enzyme of AKR1C3 gene codes in human body.This gene code by The aldehyde/ketone reducing enzyme superfamily member formed more than 40 kinds of known enzymes and protein.These enzymes by using NADH and/or NADPH is catalyzed aldehyde and ketone is converted to its correspondent alcohol as co-factor.
Relative to normal cell, many cancer cells over-express AKR1C3 reductases (referring to Cancer Res 2010； 70:1573-1584,Cancer Res 2010；66:2815-2825).Through display, PR 104：
Weaker for AKR1C3 is surveyed by matter and in clinical test in the form of water-soluble phosphoric acid salt predrug PR 104P Examination.This compound and non-selective AKR1C3 activated prodrugs, because it can also be activated under low oxygen conditions.PR l04 are tried in clinic It is invalid in testing.
There is still a need for the compound suitable for treating cancer patient, the selective AKR1C3 including being used for treating cancer patient is restored Enzyme activation prodrug.The present invention meets this demand.
Invention content
In an aspect, provided herein is the compounds with Formulas I：
Its respective pharmaceutically acceptable salt and solvate, wherein
X10For O, S, SO or SO2；
A is C6-C10Aryl, 5 to 15 unit's heteroaryls or-N=CR1R2；
R1And R2It is each independently hydrogen, C1-C6Alkyl, C3-C8Cycloalkyl, C6-C10Aryl, 4 to 15 circle heterocyclic rings, 5 to 15 Unit's heteroaryl, ether ,-CONR13R14Or-NR13COR14；
X, Y and Z is each independently hydrogen, CN, halogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C8Cycloalkyl, C6-C10Aryl, 4 to 15 circle heterocyclic rings, 5 to 15 unit's heteroaryls, ether ,-CONR13R14Or-NR13COR14；
Each R independently is hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C8Cycloalkyl, C6-C10Aryl, 4 to 15 circle heterocyclic rings, 5 to 15 unit's heteroaryls, ether ,-CONR13R14Or-NR13COR14；
R13And R14It is each independently hydrogen, C1-C6Alkyl, C3-C8Cycloalkyl, C6-C10Aryl, 4 to 15 circle heterocyclic rings, 5 to 15 Unit's heteroaryl or ether；
Wherein L1And D is defined as follows：
L1It is selected from：
R40And R41It independently is hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C8Cycloalkyl, C6-C10Aryl, 4 To 15 circle heterocyclic rings or 5 to 15 unit's heteroaryls；
R42For optionally through 1 to 3 C1-C6Alkyl-substituted C2-C3It stretches alkyl (alkylene) or stretches miscellaneous alkyl (heteroalkylene)；
V (-) is any anion, preferably pharmaceutically acceptable anion；
D is so that D-OH is the part of anticancer drug, and wherein OH is aliphatic hydroxide radical or phenolic hydroxyl group or is as provided herein It is attached to the OH parts of phosphorus atoms；Or
L1For：
R40As hereinbefore defined, R43Heterocycle is formed for hydrogen or together with D, and stretches phenyl (phenylene) part optionally Be substituted and
D is so that D-NR43H is the part of anticancer drug；Or
L1For key ,-O-CR40R41 2-、-O-C(R40R41)-NR40R41(+)-C(R40R41)-or
Wherein R40And R41As hereinbefore defined and
D is the anticancer drug containing three-level or two level nitrogen-atoms, wherein the three-level nitrogen-atoms or two level nitrogen-atoms are bonded To L1,
Wherein described alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl and ether group are optionally substituted.
In another embodiment, provided herein is the compounds with Formulas I-A
In another embodiment, X10For S.
How the illustrative and non-limiting examples and D of D are bonded to L1It provides in this article.Based on this information, ability Field technique personnel are apparent from other useful D parts according to the present invention and its and L by aobvious1It is bonded.
As used herein, D does not include amidophosphate alkylating agent, such as-P (Z1)(NR30CH2CH2X1)2、-P(Z1) (NR30 2)(N(CH2CH2X1)2)、-P(Z1)(N(CH2CH2))2Or-P (Z1)(N(CH2CH2X1)2)2, wherein each R30It independently is Hydrogen or C1-C6Alkyl or 2 R305 to 7 circle heterocyclic ring bases, Z are formed together with the nitrogen-atoms combined with it1For O or S, and X1For Cl, Br or OMs or another leaving groups.
In some embodiments, compound provided in this article has the cytotoxicity or antiproliferative effect of inhibiting tumor cell, This act as corresponding antitumor and anticancer agent DOH, the DNH utilized herein2And the like at least half, at least 20%, at least 10%th, at least 5%, at least 1% or at least 0.1%.The cytotoxic effect of measure compound or the method for antiproliferative effect are It is well known to those skilled in the art and also describe in this article.In some embodiments, those hydroxyls and amine in antitumor and anticancer agent Base (including secondary amine and three-level amido) is as provided herein generally through derivatization so that in derivatization and forms the present inventionization After closing object, the cytotoxicity or antiproliferative effect of derivative (also that is, compound provided herein) are corresponding anti-for what is utilized At least half of cancer reagent, at least 20%, at least 10%, at least 5%, at least 1% or at least 0.1%.Those skilled in the art It should be recognized which hydroxyl and/or amido (including secondary amine and three-level amido) are responsible for at least some of the reagent in antitumor and anticancer agent Or the active anticancer of a large portion.For example (and being not limited to), as provided herein, it is contemplated that in masking anthracycline Amido can reduce the cytotoxicity of anthracycline.
Compound provided in this article includes indivedual diastereoisomers and other geometric isomers and enantiomter, And the mixture of enantiomter, diastereoisomer and the geometric isomer in addition to diastereoisomer.
In another aspect, a kind of medical composition provided herein, it includes compound provided in this article and at least A kind of pharmaceutically acceptable excipient.In another aspect, be provided herein unit dose as provided herein Medical composition.
In another aspect, provided herein a kind of for treating the method for the cancer of patient, this method is included to the trouble The compound as herein provided of person's administration therapeutically effective amount or pharmaceutically acceptable composition.In one embodiment In, cancer is such a cancer, and in such cancer, AKR1C3 reductase contents are higher or higher than common content.At one In embodiment, cancer is liver cancer.In one embodiment, cancer is non-small cell lung cancer or melanoma.It, should in another aspect Method includes the AKR1C3 reductase contents that cancer is measured by using the method for AKR1C3 antibody, and when the content is equal to or greatly When predetermined value, compound provided in this article or pharmaceutically acceptable combination to patient's administration therapeutically effective amount Object.In an aspect, this method is included in before administration, is measured and is restored from AKR1C3 in the tumour in the sample that the patient detaches Enzyme content, and when the content is equal to or more than predetermined content, the patient is selected to be treated.It in some embodiments, if should Content is no more than the predetermined value or less than the predetermined value, then administration therapeutically effective amount except including administration chemical combination provided in this article Treatment of cancer outside the treatment of object or pharmaceutically acceptable composition.Those skilled in the art read the present invention after and base It will be to therapeutically effective amount, the appropriate administration pattern of determining compound provided in this article and composition in the other methods known to it Method show and be apparent from.AKR1C3 contents are to follow conventional method well known to those skilled in the art to measure.
Specific embodiment
Definition
It provides defined below to help reader.Unless otherwise defined, otherwise all technical terms used herein, symbol And other science or medical terminology or terminology are intended to what is be generally understood with the technical staff in chemistry and medical domain Meaning.In some cases, for the sake of clarity and/or for ease of reference, herein to having the meaning being generally understood Term is defined, and is included in these definition herein and be should not be construed as the term being commonly understood by expression and technique There is quite big difference in definition.
All digital indications, such as pH value, temperature, time, concentration and weight are approximation including its respective range Value, where appropriate, these approximations can usually change the increment of (+) or (-) 0.1,1.0 or 10.0.All digital indications can be with It is interpreted as before added with term " about ".Reagent described herein be illustrative and its equivalent can be in technique Know.
Unless in addition context clearly provides, otherwise " one (kind) " and " (being somebody's turn to do) " is referred to including a plurality of (kinds) Object.Therefore, for example, refer to that a kind of compound refers to one or more compounds or at least one compound.Therefore, term " one (kind) ", " one or more (kinds) " and " at least one (kind) " uses interchangeably herein.
As used herein, term "comprising" plan means that composition and method include the element, but is not excluded for other and wants Element.When for defining composition and method, " mainly by ... form ", which should mean, not to be included having the composition or method There is the other element of any basic meaning." by ... form " it should mean that advocated composition and substantive method and step do not wrap Include the other compositions element more than trace.The embodiment limited by each of these variation terms is in scope of the invention It is interior.Therefore, it is contemplated that these method and compositions may include other step and component (including) or alternatively include unessential Step and composition (mainly by ... form) are alternatively intended merely to stated method and step or composition (by ... group Into).
In the preceding " C of groupx-Cy" or " Cx-y" refer to the range of amount of carbon atom present in the group.For example, C1-C6Alkyl refers to the alkyl at least one and most 6 carbon atoms.
" alkoxy " refers to-O- alkyl.
" amido " refers to NRpRq, wherein RpAnd RqIt independently is hydrogen or C1-C6Alkyl or RpAnd RqIt is former with its bonded nitrogen Son forms 4 to 15 circle heterocyclic rings together.
" alkyl " refers to the monovalent saturation with 1 to 10 carbon atom and in some embodiments with 1 to 6 carbon atom Aliphatic hydrocarbyl.“Cx-yAlkyl " refers to the alkyl with x to y carbon atom.For example, this term includes straight chain and branched chain Alkyl, such as methyl (CH3), ethyl (CH3CH2), n-propyl (CH3CH2CH2), isopropyl ((CH3)2CH-), normal-butyl (CH3CH2CH2CH2), isobutyl group ((CH3)2CHCH2), sec-butyl ((CH3)CH3CH2) CH-), tertiary butyl ((CH3)3C-), just Amyl (CH3CH2CH2CH2CH2) and neopentyl ((CH3)3CCH2-)。
" stretching alkyl (Alkylene) " refers to 1 to 10 carbon atom and in some embodiments with 1 to 6 carbon original The divalent radical of saturated aliphatic alkyl of son.“Cu-vStretch alkyl " refer to have u to v carbon atom stretch alkyl.Alkylidene (Alkylidene) it and stretches alkyl (Alkylene) and includes branched chain and straight-chain alkyl.For example, " C1-6Stretch alkyl " including Asia Methyl, stretch ethyl (ethylene), stretch propyl (propylene), 2- methyl stretches propyl (2-methypropylene), stretches amyl (pentylene) and similar to group." stretching miscellaneous alkyl " refers to hetero atom of the chain carbon atom through such as O, S, N or P or containing miscellaneous original Alkyl is stretched in the substituent group displacement of son.
" alkenyl " refers to 2 to 10 carbon atoms and in some embodiments with 2 to 6 carbon atoms or 2 to 4 carbon Atom and at least one vinyl unsaturated sites (>C=C<) straight chain or branch's chain alkylene.For example, Cx-yAlkenyl Refer to that there is the alkenyl of x to y carbon atom, and be intended to include such as vinyl, acrylic, 1,3-butadiene base and similar base Group." stretching alkenyl (alkenylene) " refers to the divalent alkenyl with appropriate hydrogen content." stretch miscellaneous thiazolinyl (heteroalkenylene) " refer to hetero atom of the chain carbon atom through such as O, S, N or P or replaced containing heteroatomic substituent group Alkenylene.
" amidophosphate alkylating agent " refers to be bonded to-O-P (Z comprising one or more1) part Z5-X5-Y5Partial Alkylating agent, wherein Z5For hetero atom, such as nitrogen, sulphur or oxygen；X5Ethyl is stretched for what is be optionally substituted；Y5For halogen or another Leaving group；Or Z5-X5-Y5Aziridinyl (NCH is formed together2CH2) part, and Z1As hereinbefore defined.Such alkylating agent It can be with DNA or another nucleic acid or albumen qualitative response.In some cases, alkylating agent can be crosslinked with DNA.
" alkynyl " refers to 2 to 10 carbon atoms and in some embodiments with 2 to 6 carbon atoms or 2 to 4 carbon originals Son and containing the linear monovalent hydrocarbon radical of at least one three key or branched chain univalence hydrocarbyl.Term " alkynyl " is also intended to include having one The alkyl of a three key and a double bond.For example, C2-6Alkynyl includes acetenyl, propinyl and similar group." stretch alkynyl (alkynylene) " refer to that there is the divalent alkynyl radical of appropriate hydrogen content." stretching miscellaneous alkynyl (heteroalkynylene) " refers to chain Hetero atom of the carbon atom through such as O, S, N or P stretches alkynyl containing the displacement of heteroatomic substituent group.
" aryl " refers to 6 to 14 carbon atoms and without ring hetero atom and with single ring (such as phenyl) or multiple It is condensed the aromatic group of (condensed) ring (such as naphthalene or anthryl).For multi-loop system, including having the virtue for being free of ring hetero atom The condensed of race and non-aromatic ring, bridging and spiral ring system, when attachment point is located at aromatic carbon atom, applicable term " aryl " or " Ar " (such as 5,6,7,8- naphthane -2- bases due to its attachment point be aryl at 2 of aromatics phenyl ring)." stretch aryl (arylene) " refer to that there is the divalent aryl of appropriate hydrogen content.
" cycloalkyl " refer to 3 to 14 carbon atoms and without ring hetero atom and with single ring or multiple rings (including Condensed, bridging and spiral ring system) saturation or fractional saturation cyclic group.The aromatics of ring hetero atom and non-aromatic is free of for having The multi-loop system of race's ring when attachment point is located at non-aromatic carbon atom (such as 5,6,7,8,-naphthane -5- bases), is applicable in art Language " cycloalkyl ".Term " cycloalkyl " is including cycloalkenyl group.The example of cycloalkyl include for example adamantyl, cyclopropyl, cyclobutyl, Cyclopenta, cyclooctyl and cyclohexenyl group." stretching cycloalkyl (cycloalkylene) " refers to there is the divalent cycloalkyl of appropriate hydrogen content Base.
" ether " refers to through 1 to 3 C1-C6The C of alkoxy substitution1-C6Alkyl, wherein alkoxy refer to-O- alkyl.
" halogen " refers to one or more of fluorine, chlorine, bromine and iodine.
" heteroaryl " refers to 1 to 14 carbon atom and 1 to 6 selected from the hetero atom of group being made of oxygen, nitrogen and sulphur Aromatic group and including monocyclic (for example, imidazole radicals -2- bases and imidazoles 5- yls) and multi-loop system (for example, imidazopyridyl, Benzotriazole base, benzimidazolyl-2 radicals-base and benzimidazole -6- bases).For multi-loop system, including with aromatics and non-aromatic ring Condensed, bridging and spiral ring system, if there are at least one ring hetero atom and attachment point at the atom of aromatic ring (such as 1,2, 3,4- tetrahydroquinoline -6- bases and 5,6,7,8- tetrahydroquinoline -3- bases), then applicable term " heteroaryl ".In some embodiments, One or more nitrogen and/or sulphur annular atom of heteroaryl are optionally oxidized to obtain N- oxides (N → O), sulfinyl or sulphur Acyl moiety.Term heteroaryl includes but is not limited to acridinyl, azocine base (azocinyl), benzimidazolyl, benzo furan It mutters base, benzo thio-furan base, benzothienyl (benzothiophenyl), benzoxazolyl, benzothiazolyl, benzo three Oxazolyl, benzo tetrazole radical, benzo isoxazolyl, benzisothia oxazolyl, benzothienyl (benzothienyl), benzimidazoline Base, NH- carbazyls, carboline base, chromanyl (chromanyl), benzopyranyl (chromenyl), is scolded at carbazyl Quinoline base (cinnolinyl), dithiazine base, furyl, furan Xanthones bases, imidazoles piperidinyl, imidazolinyl, imidazopyridyl, imidazoles Base, indazolyl, indolinyl (indolenyl), indoline base, indolizine base, indyl, isobenzofuran-base, different benzo two Hydrogen pyranose (isochromanyl), iso indazolyl, isoindoline base, isoindolyl, isoquinolyl (isoquinolinyl), Isoquinolyl (isoquinolyl), isothiazolyl, isoxazolyl, naphthyridines base, octahydro isoquinolyl, oxadiazoles base, oxazole pyridine Base, oxazolyl, pyrimidine radicals, coffee piperidinyl, coffee quinoline base, phenazinyl, phenothiazinyl, phenoxazine thiophene base, phenoxazine base, phthalazinyl, hexahydro Pyrazinyl, pteridine radicals, purine radicals, pyranose, pyrazinyl, pyrazoles piperidinyl, pyrazolinyl, pyrazolyl, clatter piperazine base, pyrido oxazole Base, pyridine-imidazole base, pyridothiazole base, pyridyl group (pyridinyl), pyridyl group (pyridyl), pyrimidine radicals, pyrrole radicals, Quinazolyl, quinolyl, quinoline quinoline base, quininuclidinyl (quinuclidinyl), tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazolium Base, thiadiazine base, thiadiazolyl group, thianthrene group, thiazolyl, thienyl (thienyl), thiophene benzothiazolyl, thieno oxazolyl, Thienoimidazole base, thienyl (thiophenyl), triazine radical and xanthyl (xanthenyl)." stretch heteroaryl (heteroarylene) " refer to that there is the divalent heteroaryl radical of appropriate hydrogen content.
" heterocycle " or " heterocycle " or " Heterocyclylalkyl " or " heterocycle " refer to there is 1 to 14 carbon atom and 1 to 6 choosing The heteroatomic saturation or fractional saturation cyclic group of the group of free nitrogen, sulphur or oxygen composition and including monocyclic and multi-loop system, are wrapped Include condensed, bridging and spiral ring system.For the multi-loop system with aromatics and/or non-aromatic ring, when there are at least one ring is miscellaneous Atom and attachment point be located at the atom of non-aromatic ring (for example, 1,2,3,4- tetrahydroquinoline -3- bases, 5,6,7,8- tetrahydroquinolines - 6- bases and decahydroquinoline -6- bases) when, applicable term " heterocycle ", " heterocycle ", " Heterocyclylalkyl " or " heterocycle ".In some realities It applies in example, heterocyclic group is 3 to 15 yuan, 4 to 14 yuan, 5 to 13 yuan, 7 to 12 yuan or 5 to 7 circle heterocyclic rings herein.At some its In his embodiment, heterocycle contains 4 hetero atoms.In some other embodiments, heterocycle contains 3 hetero atoms.In another implementation In example, heterocycle contains most 2 hetero atoms.In some embodiments, the nitrogen-atoms of heterocycle and/or sulphur atom are optionally through oxygen Change to provide N- oxides, sulfinyl or sulfonyl moieties.Heterocycle includes but is not limited to THP trtrahydropyranyl, hexahydropyridine Base, N- methyl piperidine -3- bases, hexahydropyrazine base, N- methylpyrrole pyridine -3- bases, 3- pyrroles's piperidinyl, 2- Pyrrolizidine ketone -1- Base, morpholinyl and pyrroles's piperidinyl.Instruction carbon atom number purpose prefix (such as C3-10) refer to the atomicity that cleans in heterocyclyl moieties The total number of carbon atoms other than mesh.Divalent heterocyclic group will be with the hydrogen content suitably adjusted.
" leaving group " refer to can under nucleophilic displacement conditions well known to those skilled in the art the part through displacement.It leaves away Group includes but is not limited to halogen and-OSO2-R20, wherein R20For alkyl, aryl, cycloalkyl, the heterocycle being optionally substituted Base or heteroaryl.
The group that term " being optionally substituted " refers to be substituted or be unsubstituted.The group can be through one or more substitutions Base, such as 1,2,3,4 or 5 substituent group substitution.Preferably, these substituent groups are selected from the group being made up of：Side oxygroup, halogen Base ,-CN, NO2、-N2+、-CO2R100、-OR100、-SR100、-SOR100、-SO2R100、-NR100SO2R100、-NR101R102、- CONR101R102、-SO2NR101R102、C1-C6Alkyl, C1-C6Alkoxy ,-CR100=C (R100)2、-CCR100、C3-C10Cycloalkyl, C3-C10Heterocycle, C6-C12Aryl and C2-C12Heteroaryl or divalent substituent, such as-O- (CH2)-O-、-O-(CH2)2- O- and It is through 1 to 4 methyl substituted form, wherein R100、R101And R102It is each independently hydrogen or C1-C8Alkyl；C3-C12Cycloalkanes Base；C3-C10Heterocycle；C6-C12Aryl；Or C2-C12Heteroaryl；Or R101And R1025 to 7 are formed together with the nitrogen-atoms being attached with it Circle heterocyclic ring；Wherein alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are respectively optionally through 1 to 3 halogen, 1 to 3 C1-C6Alkane Base, 1 to 3 C1-C6Alkylhalide group or 1 to 3 C1-C6Alkoxy replaces.Preferably, these substituent groups are selected from what is be made up of Group：Chlorine, fluorine ,-OCH3, methyl, ethyl, isopropyl, cyclopropyl ,-CO2H and its salt and C1-C6Arrcostab, CONMe2、CONHMe、 CONH2、-SO2Me、-SO2NH2、-SO2NMe2、-SO2NHMe、-NHSO2Me、-NHSO2CF3、-NHSO2CH2Cl、-NH2、-OCF3、- CF3And-OCHF2。
To patient's " administration (Administering) " drug or drug to patient " administration (administration Of) " (and grammatical equivalent of this phrase) refers to direct administration, this can be from medical professional to patient's administration or can be certainly Dispensing；And/or indirect administration, this can be the operation for issuing drug prescription.For example, introduction patient from administration drug and/or Physician who has given the drug is by drug administration patient.
" cancer " refer to can by invasion local wide and by transfer systemically expand and may indeterminate growth it is white Blood disease, lymthoma, carcinoma and other malignant tumours, including entity tumor.The example of cancer include but is not limited to adrenal, Osteocarcinoma, the cancer of the brain, breast cancer, bronchiolar carcinoma, colon cancer and/or the carcinoma of the rectum, gallbladder cancer, incidence cancer, kidney, laryngocarcinoma, liver cancer, lung Cancer, nerve fiber cancer, cancer of pancreas, prostate cancer, accessory thyroid glands cancer, cutaneum carcinoma, gastric cancer and thyroid cancer.Cancer it is certain other Example includes acute and chronic lymphatic ball and particle ball tumour, gland cancer, adenoma, basal-cell carcinoma, cervix dysplasia And carcinoma in situ, ewing's sarcoma (Ewing's sarcoma), epidermoid, giant-cell tumor, polymorphism spongioblast Knurl, hair cell tumour, enteric ganglia cytoma, Hypertrophic corneal nerve tumour, islet cells carcinoma, Kaposi sarcoma (Kaposi's sarcoma), liomyoma, leukaemia, lymthoma, carcinoid malignant knurl, malignant mela noma, hypercalcemia of malignancy Disease, Malaysia side sample build tumour (marfanoid habitus tumor), marrow sample epithelioma, metastatic cutaneum carcinoma, mucous membrane nerve Knurl, myeloma, mycosis fungoides, spongioblastoma, osteosarcoma, osteogenic and other sarcomas, ovarioncus, pheochromocytoma, The squamous cell carcinoma of both true property erythremia, primary brain tumor, Small Cell Lung Cancer, ulcer type and nipple type, hyperplasia, essence It is archaeocyte knurl, soft tissue sarcoma, retinoblastoma, rhabdomyosarcoma, renal cell carcinoma, local skin lesion, netted thin Born of the same parents' sarcoma and Wilm'stumor (Wilm's tumor).
Be used herein as a part for D parts " drug " include but is not limited to gemcitabine (gemcitabine), Erlotinib (erlotinib), Meturedepa (meturedepa), uredepa (uredepa), hemel (altretamine), Imatinib (imatinib), tretamine (triethylenemelamine), front three melamine, benzenebutanoic acid Mustargen (chlorambucil), Chlornaphazine (chlornaphazine), estramustine (estramustine), Gefitinib (gefitinib), mustargen (mechlorethamine), mustargen oxide hydrochloride, melphalan (melphalan), novoembichin (novembichin), Fen Siterui (phenesterine), pennisetum mustard (prednimustine), Trofosfamide (trofosfamide), uracil mastard (uracil mustard), Carmustine (carmustine), chlorozotocin (chlorozotocin), Fotemustine (fotemustine), Nimustine (nimustine), Ranimustine (ranimustine), Dacarbazine (dacarbazine), mannomustine (mannomustine), dibromannitol (mitobronitol), mitolactol (mitolactol), pipobroman (pipobroman), aclacinomycin (aclacinomycins), actinomycin (actinomycin), Anthramycin (anthramycin), azo silk amino acid (azaserine), bleomycin (bleomycin), act-C (cactinomycin), Carubicin (carubicin), Carzinophillin (carzinophilin), chromomycin (chromomycin), D actinomycin D d (dactinomycin), daunomycin (daunorubicin), daunorubicin (daunomycin), 6- diazonium-5- sides Oxy-1-just white amino acid, mycophenolic acid (mycophenolic acid), nogalamycin (nogalamycin), olivomycin (olivomycin), Peplomycin (peplomycin), plicamycin (plicamycin), porfiromycin (porfiromycin), puromycin (puromycin), broneomycin (streptonigrin), streptozotocin (streptozocin), tubercidin (tubercidin), ubenimex (ubenimex), Zinostatin (zinostatin), a left side are soft than star (zorubicin), Di Nuo Special peaceful (denopterin), pteropterin (pteropterin), Trimetrexate (trimetrexate), fludarabine (fludarabine), Ismipur, Tiamiprine (thiamiprine), thioguanine, ancitabine (ancitabine), Azacitidine (azacitidine), 6- aza uridines, Carmofur (carmofur), cytarabine (cytarabine), double deoxidations Uridine (dideoxyuridine), doxifluridine (doxifluridine), enocitabine (enocitabine), floxuridine (floxuridine), (pulmozyme), vinegar Portugal when 5 FU 5 fluorouracil, Tegafur (tegafur), L-ASP, hundred admire Aldehyde lactone, aldophosphamideglycoside, amido levulic acid, amsacrine (amsacrine), bass cloth western (bestrabucil), than life Group (bisantrene), Buddhist amide (defofamide), demecolcine (demecolcine), diaziquone (diaziquone), End not bird amino acid (elfornithine), Elliptinium Acetate (elliptinium acetate), ethoglucid (etoglucid), fluorine His amine (flutamide), hydroxycarbamide (hydroxyurea), interferon-' alpha ', interferon-beta, interferon-γ, be situated between white element -2, mushroom Mushroom polysaccharide (lentinan), methyl-GAG (mitoguazone), mitoxantrone (mitoxantrone), Mopidamol (mopidamol), C-283 (nitracrine), Pentostatin (pentostatin), egg amine mustargen (phenamet), Pirarubicin (pirarubicin), podophyllic acid (podophyllinic acid), 2- ethylhydrazides, procarbazine (procarbazine), razoxane (razoxane), Sizofiran (sizofiran), Spirogermanium (spirogermanium), too Flat ocean taxol (paclitaxel), tamoxifen (tamoxifen), Erlotinib (erlotonib), Teniposide (teniposide), tenuazonic acid (tenuazonic acid), triethyleneiminobenzoquinone, 2,2', 2 "-trichlorotriethylamine, urine Alkane, vincaleukoblastinum (vinblastine) and vincristine (vincristine).
" patient " is interchangeably used with " individual ", to refer to the mammal for needing treatment of cancer.Patient is generally people Class.Patient generally suffers from the mankind of cancer after diagnosing.In certain embodiments, " patient " or " individual " can refer to sieve Choosing, characterization and evaluation drug and the non-human mammal of therapy, such as non-human primate, dog, cat, rabbit, pig, mouse Or rat.
" prodrug " refers to be metabolized after administration or be otherwise converted to about at least one characteristic there is biology to live The compound of property or more active compound (or drug).Relative to drug, prodrug is so that it is relatively low relative to pharmaceutical activity Or inactive mode is through chemical modification, and chemical modification causes after the administration prodrug, by metabolism or other biological Process generates relative medicine.Relative to active medicine, prodrug can have the metabolic stability changed or K+transport, less secondary work With or low toxicity or improvement fragrance (for example, with reference to bibliography Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, the 388-392 pages, with the side of reference Formula is incorporated herein).The reactant in addition to relative medicine can be used to synthesize for prodrug.
" entity tumor " refers to a variety of entity tumors, including but not limited to bone, brain, liver, lung, lymph node, pancreas, preceding Metastatic tumo(u)r in row gland skin and soft tissue (sarcoma).
" therapeutically effective amount " of drug refers to will there is predetermined treatment effect as administration cancer patient, such as alleviate, change It is apt to, mitigates or eliminates the amount of one or more performances of the cancer of the patient.Therapeutic effect may not necessarily be sent out in administration dose It is raw, thereby increases and it is possible to only to occur after a series of dosage of administration.Therefore, administration therapeutically effective amount can be carried out by dispensing one or more times.
" treatment (treating) " patient's condition or patient, the patient's condition or patient " treatment (treatment of) " or the patient's condition or Patient " therapy (therapy of) " refers to take steps to obtain beneficial or required as a result, including clinical effectiveness.Go out In the purpose of the present invention, beneficial or required clinical effectiveness include but is not limited to one or more symptoms of cancer alleviation or Improve；The mitigation of disease degree；The delay of progression of disease slows down；Improvement, mitigation or the stabilisation of morbid state；Or other have The result of benefit.In some cases, the treatment of cancer can cause partial reaction or stable disease.
" tumour cell " refers to any appropriate species, such as mammal, such as muroid, canine animals, cats animal, horse The tumour cell of class animals or humans.
Illustrative embodiment
The compound with Formulas I as disclosed provided herein.
In one embodiment, Z is hydrogen.In another embodiment, X is hydrogen.In another embodiment, Y is hydrogen.Another In embodiment, Y is halogen.
In some embodiments, each R is hydrogen.In some embodiments, single R is hydrogen and another R is such as this paper institutes The non-hydrogen substituent of offer.In some embodiments, each R is non-hydrogen substituent as herein provided.In some embodiments In, R C1-C6Alkyl.In some embodiments, R is methyl.
In some embodiments, R40、R41And R43It independently is hydrogen.In some embodiments, R40、R41And R43It independently is Methyl.In some embodiments, R42For-CH2-CH2-.In some embodiments, R42For-CH2-C(Me)2-.In one embodiment In, the carbon atom bonding with dimethyl is connected to linking group L1Rest part, which is then bonded to drug moiety D。
In another embodiment, A is the C being optionally substituted6-C10Aryl.In another embodiment, A is optionally passes through Substituted phenyl.In another embodiment, phenyl optionally replaces through 1 to 3,1 to 2 or single substituent group, the substituent group Selected from halogen ,-CN, NO2、-COR100、-CO2R100、-OR100、-SR100、-SOR100、-SO2R100、-NR100SO2R100、- NR101R102、-CONR101R102、-SO2NR101R102、C1-C6Alkyl, C1-C6Alkoxy, C3-C10Cycloalkyl, C3-C10Heterocycle, C6-C12Aryl and C2-C12Heteroaryl or divalent substituent, such as-O- (CH2)-O-、-O-(CH2)2- O-, wherein R100、R101And R102It is each independently hydrogen or C1-C8Alkyl；C3-C12Cycloalkyl；C3-C10Heterocycle；C6-C12Aryl；Or C2-C12Heteroaryl； Or R101And R102With forming 5 to 7 circle heterocyclic rings together with the nitrogen-atoms attached by it；Wherein alkyl, cycloalkyl, heterocycle, aryl or Heteroaryl is respectively optionally through 1 to 3 halogen, 1 to 3 C1-C6Alkyl, 1 to 3 C1-C6Alkylhalide group or 1 to 3 C1-C6Alcoxyl Base replaces.In another embodiment, A is phenylbenzene.
In another embodiment, A is 5 to 15 unit's heteroaryls being optionally substituted.In another embodiment, A is regarding feelings The pyridyl group that condition is substituted.In another embodiment, A is the benzothiazolyl being optionally substituted.In another embodiment, A For quinolyl.
In another embodiment, A is-N=CR1R2, wherein R1And R2As defined herein.
In certain embodiments, one of certain suitable substituent groups of A as specific compound provided below is disclosed Point.
In some embodiments, the non-limiting examples of V (-) include halogen ion, alkyl or aryl sulfonate radical, carboxylate radical and Analog.Alkyl or aryl sulfonate radical includes but is not limited to or MeSO3Or TsO-.Carboxylate radical includes but is not limited to acetic acid Root or formate.
In one embodiment, D parts are a following part：SN-38, Irinotecan (irinotecan), topology are replaced Health (topotecan), camptothecine (camptothecin) or other such 1 inhibitor of quinolyl topoisomerase；Bendamustine Spit of fland (bendamustine)；Blood vessel structure disrupting agent；Doxorubicin (doxorubicin), daunomycin (daunorubicin), Or another anthracycline (anthracycline)；Pemetrexed (pemetrexed)；Vorinostat (vorinostat)；Come that Spend amine (lenalidomide) or another Distaval (thalidomide) derivative；Jia Litepi (ganetespib)；Polyenoid Taxol (docetaxel), Paclitaxel or another taxol；17-AAG；5-FU, gemcitabine, purinethol (6- MP, Purinethol), fluorouracil (5-FU, Adrucil), thioguanine (6-TG, Thioguanine), cytarabine (Cytosar-U, DepoCyt), floxuridine (FUDR), fludarabine (fludarabine) (Fludara), azacytidine (Vidaza), Pentostatin (Nipent), Cladribine (cladribine) (Leustatin, 2-CdA), gemcitabine (Gemzar) and capecitabine (capecitabine) (Xeloda) and other such nucleoside derivates；Abiraterone (abiraterone)；Imatinib (imatinib), nilotinib (nilotinib), Erlotinib (erlotinib), Suo La Non- Buddhist nun (sorafenib), Sutent (sunitinib), Gefitinib (gefitinib), Lapatinib (lapatinib), Dasatinib (dasatinib), Bosutinib (bosutinib), Ponatinib (ponatinib), according to Shandong replace Buddhist nun (ibrutinib), Afatinib (afatinib), dabrafenib (dabrafenib), card it is rich for Buddhist nun (cabozantinib), it is auspicious Ge Feini (regorafenib), Pa Zuo dissolve Buddhist nun (pazopanib), Axitinib (axitinib), reed can replace Buddhist nun (ruxolitinib), gram Zhuo is for Buddhist nun (crizotinib), Wei Luofeini (vemurafenib), Vande Thani (vandetanib).In certain embodiments, a part of the D parts for some drugs as explained further on.
In one embodiment, L1For
In another embodiment, L1For：
In another embodiment, L1For：
In another embodiment, L1For：
In another embodiment, L1For：
In another embodiment, L1For：
In another embodiment, L1For：
In another embodiment, L1For：
In another embodiment, L1For：
In another embodiment, L1For key.In another embodiment, L1For-O-C (R40R41)2-.In another embodiment, L1For：
In one embodiment, the compound provided herein with formula 1A-1：
Wherein parameter is as defined in any of the above aspect and embodiment.About D, HNR43- D is contains level-one amido or two The cytotoxic agent of grade amido.
In one embodiment, the compound provided herein with formula 1A-2：
Wherein parameter is as defined in any of the above aspect and embodiment.About D, HO-D is contains at least one hydroxyl Cytotoxic agent.
In one embodiment, the compound provided herein with formula 1A-3：
Wherein parameter is as defined in any of the above aspect and embodiment.About D, HO-D is contains at least one hydroxyl Cytotoxic agent.
In one embodiment, the compound provided herein with formula 1A-4：
Wherein parameter is as defined in any of the above aspect and embodiment, and about D, and HO-D is contains at least one hydroxyl Cytotoxic agent.
In one embodiment, the compound provided herein with formula 1A-5：
Wherein parameter is as defined in any of the above aspect and embodiment.
In one embodiment, the compound provided herein with formula 1A-6
Wherein parameter is as defined in any of the above aspect or embodiment and D is the drug containing two level nitrogen-atoms, wherein The two level nitrogen-atoms is bonded to methylene, as shown above.
In one embodiment, the compound provided herein with formula 1A-7
Wherein parameter is as defined in any of the above aspect or embodiment and D is the drug containing two level nitrogen-atoms, wherein The two level nitrogen-atoms is bonded to methylene, as shown above.
In one embodiment, the compound provided herein with formula 1A-8
It is medicine wherein together with pyridine moiety of the parameter as defined in any of the above aspect or embodiment and attached by D is with it Object, the wherein nitrogen-atoms are bonded to methylene, as shown above.
In one embodiment, the compound provided herein with formula 1A-9
Wherein parameter is as defined in any of the above aspect or embodiment and D is the drug containing hydroxyl.
In one embodiment, the compound provided herein with formula 1A-10
Wherein parameter is as defined in any of the above aspect and embodiment.About D, HNR43- D is contains level-one amido or two The cytotoxic agent of grade amido.
In other embodiments ,-O-A parts as indicated above are through another-X as herein provided10Part A is put It changes.
In certain embodiments, a part of the D parts for some drugs as explained further on.
In one embodiment, the compound provided herein with following formula：
Wherein each R60The alkyl or aryl sulphonic acid ester for independently being halogen or being optionally substituted, and R65For C1-C6Alkane Base, preferably methyl.
In one embodiment, the compound provided herein with following formula：
In one embodiment, compound provided herein has following formula：
In one embodiment, compound provided herein has following formula：
In one embodiment, compound provided herein has following formula：
In one embodiment, compound provided herein has following formula：
In one embodiment, compound provided herein has following formula：
In another embodiment, compound disclosed below provided herein or its is respective pharmaceutically acceptable Salt or solvate.In one embodiment, these compounds include taxol as antitumor and anticancer agent：
In one embodiment, these compounds include nucleosides antitumor and anticancer agent：
In one embodiment, these compounds include anthracycline derivatives (all as shown below) and are tried as anticancer Agent：
In one embodiment, these compounds include camptothecin derivative, and such as SN-38 and other such compounds are made For antitumor and anticancer agent：
In one embodiment, compound includes alkylation antitumor and anticancer agent, such as mustargen：
In one embodiment, the compound includes Etoposide as antitumor and anticancer agent：
In one embodiment, these compounds include tubulin targeting agent, he take charge of more pavilions (tasidotin) and difficult to understand auspicious Statin (auristatin) is as anticancer drug：
In one embodiment, these compounds include kinase inhibitor as antitumor and anticancer agent：
In one embodiment, these compounds include Qingsong Liu et al. people, Chem Biol., 2013,20 (2), The prodrug of other irreversible kinase inhibitors described in the 146-159 pages.
The example of compound provided in this article also includes those compounds disclosed in examples section below.
In another aspect, a kind of method for preparing the compound with Formulas I provided herein, it includes make with Formula II Compound：
Wherein L is leaving group；With the compound with formula III：
And optionally existing alkali contact, to obtain the compound with Formulas I, wherein remaining parameter such as any aspect above Or defined in embodiment.
In one embodiment, L is halogen.In another embodiment, L F.In another embodiment, X10For O.Another In one embodiment, Z is hydrogen.In another embodiment, X is hydrogen.In another embodiment, Y is hydrogen.In another embodiment, Y is Halogen.In one embodiment, the non-nucleophilic highly basic that alkali is well known to those skilled in the art.In one embodiment, alkali For hydride base.
Prepare compound provided in this article illustrative and non-limiting method show it is as follows：
Compound or " three-level " benzyl compounds containing 2 non-hydrogen R groups can be similarly by using corresponding tertiary alcohol And/or prepared by halide and other such three-level benzyl initial substances.Those skilled in the art after reading this disclosure will It shows and is apparent from, there are other compounds of other linking groups and other drugs the method preparation can be used.
The certain methods provided herein for being used to synthesize compound provided in this article.Those skilled in the art are based on being directed to The replacement of the reorganization of synthetic method known to it and wherein reagent and reactant is apparent from being carried herein for synthesizing by aobvious The other methods of these and other compound supplied.See, for example, Hay et al., J.Med.Chem.2003,46,2456-2466, 21 (2011) 3986-3991 and WO of Hu et al., Bioorganic＆Medicinal Chemistry Letters 2008151253.It is commercially available or conventional method system can be followed available for preparing the initial substance of compound provided in this article It is standby.Reaction is carried out usually in atent solvent and is heated when necessary.Person skilled in the art will readily appreciate that certain reactions It may need to use protecting group.Protecting group is well-known to those skilled in the art and is described in such as Greene's Protective Groups in Organic Synthesis.Peter G.M.Wuts and Theodora W.Greene, 4th edition or later release, in John Wily＆Sons, Inc., 2007.Reaction product can follow conventional method, such as crystallize, is heavy It forms sediment, distillation and/or chromatography are detached.Well-known process can be used in compound or the purity of intermediary, such as1H-NMR、 HPLC, TLC and similar approach determine.
Example
Example 1：Synthesize compound provided in this article
A.
Compound B
By compound A (110mg) in 5ml SOCl at 90 DEG C2In solution heat 3 hours.Then remove under vacuum Solvent.Residue is dissolved in toluene (5ml) and removes solvent again, compound B (112mg) is obtained, without further Purifying.
Compound D
It is at 80 DEG C that the solution heating of compound B (80mg), compound C (2mL) in ACN (acetonitrile, 2ml) is overnight. Solvent is removed under vacuum.Chromatography (ACN is carried out to residue on silica gel:H2O=80:20 (V/V)), obtain 65mgization Close object D.
TH2995
By compound D (60mg) in 5ml SOCl at 90 DEG C2In solution heat 4 hours.Then remove under vacuum Solvent.Chromatography (AcOEt is carried out to residue on silica gel:MeOH=90:10 (V/V)), obtain 50mg TH2995. 1HNMR(CDCl3+CD3OD):7.94(1H),7.38(2H),7.18(2H),7.04(3H),4.70(2H),3.96(3H),3.56 (4H),2.86(4H)。
B.
At 0 DEG C, to compound 1 (0.16g, 0.5mmol), SN-38 (0.23g, 0.6mmol) and PPh3(0.26g, DIAD (0.2g, 1mmol) 1mmol) is added in the suspension in THF (5mL).Reaction mixture is made to be warming up to room temperature and stirring It is overnight, it is purified by flash chromatography on silica, obtains compound 2.1H NMR (DMSO-d6) δ 8.16 (1H, d, J=9.2Hz), 8.08 (1H, d, J=9.2Hz), 7.62-7.52 (6H, m), 7.42 (2H, t, J=8Hz), 7.34-7.3 (2H, m), 7.27 (1H, S), 7.07 (2H, d, J=8.4Hz), 6.48 (1H, s), 5.49 (2H, s), 5.43 (2H, s), 5.22 (2H, s), 3.1 (2H, q, J =7.6Hz), 1.87 (2H, m), 1.18 (3H, t, J=7.6Hz), 0.877 (3H, t, J=7.2Hz), 696.5 (M of m/z (ESI)+ +H)。
C.
Under argon gas, at 0 DEG C triethylamine is added into solution of the alcohol 3 (0.6g, 2mmol) in DCM (10mL) (0.57mL, 4mmol) and p-NCF (0.6g, 3mmol).Reaction mixture is made to be warming up to room temperature and stirred overnight.With water, saturation NaHCO3And brine washing reaction mixture.Organic layer is through Na2SO4It is dry, it is concentrated under reduced pressure.Residue is by silica gel column chromatography Method purifies, and obtains required PNP carbonic esters.Amine 6 (0.38g, 2mmol), DIPEA are added in PNP carbonic esters into THF (10mL) (0.5mL, 3mmol) and DMAP (0.1g) and the solution is stirred at room temperature 2 hours.Decompression concentrated solution and residue is by silicon Glue flash chromatography obtains compound 4.1H NMR(CDCl3) δ 8.9 (1H, s), 8.16 (1H, d, J=8.4Hz), 8.1- 8.0 (2H, m), 7.52 (1H, dd, J=9,2.6Hz), 7.43 (1H, dd, J=8,4.2Hz), 7.36-7.3 (1H, m), 7.07 (1H,s),7.03(1H,s),5.11(2H,s),3.4-3.1(4H,m),3.0-2.7(6H,m),1.42(9H,s),m/z(ESI) 511.2(M++H)。
HCl solution (4M dioxanes, 1mL) is added into the solution of compound 4 (150mg, 0.3mmol) and in environment At a temperature of stirring mixture 3 hours.Solvent is removed under reduced pressure, obtains thick amine salt, is directly used in following reaction.m/z (ESI)411.1(M++H)。
Amine salt is suspended in CH2Cl2In (2mL), be cooled to 0 DEG C and addition phosgene (15% in toluene, 0.26mL, 0.36mmol), triethylamine (0.14mL, 1mmol) is then added.After 1 hour, by Paclitaxel (0.17g, 0.2mmol) added in reaction mixture, DMAP (0.12g, 1mmol) is then added.Make reaction mixture be warming up to room temperature and Stirred overnight.Decompression concentrated solution and residue is purified by flash chromatography on silica, obtains compound 5.m/z(ESI) 1290.7(M++H)。
D.
It is initial substance with alcohol 7, prepare compound 9.m/z(ESI)1305.2(M++H)。
Under argon gas, at 0 DEG C triethylamine is added into solution of the alcohol 10 (0.5g, 3mmol) in DCM (15mL) (0.85mL, 6mmol) and p-NCF (0.9g, 4.5mmol).Reaction mixture is made to be warming up to room temperature and stirred overnight.With water, satisfy And NaHCO3And brine washing reaction mixture.Organic layer is through Na2SO4It dries and is concentrated under reduced pressure.Residue is by layer of silica gel Analysis method purifies, and obtains required PNP carbonic esters.In PNP carbonic esters into THF (10mL) add amine 6 (0.57g, 3mmol), DIPEA (0.75mL, 4mmol) and DMAP (0.1g) and the solution is stirred at room temperature 2 hours.Decompression concentrated solution and residue It is purified by flash chromatography on silica, obtains compound 11.1H NMR(CDCl3)δ8.12-8.04(1H,m),7.38-7.2(2H, m),5.19(2H,s),3.5-3.3(4H,m),3.1-2.8(6H,m),1.45(9H,s)。
At room temperature by compound 11 (0.58g, 1.5mmol), K2CO3(0.41g, 3mmol) and 4- phenylphenols The mixture stirred overnight of (0.38g, 2.25mmol) in DMF (5ml).Reaction mixture is diluted with EtOAc and with water, brine Washing.Organic layer is through Na2SO4It dries and is concentrated under reduced pressure.Residue is purified by silica gel chromatography, obtains compound 12.1H NMR(CDCl3) δ 7.99 (1H, d, J=8.4Hz), 7.64-7.54 (4H, m), 7.45 (2H, t, J=7.6Hz m), 7.36 (1H, T, J=7.6Hz), 7.2-7.15 (1H, m), 7.13 (2H, d, J=8.8Hz), 7.03 (1H, s), 5.1 (2H, m), 3.5-3.2 (4H,m),3.0-2.7(6H,m),1.42(9H,s),m/z(ESI)536.4(M++H)。
HCl solution (4M dioxanes, 1mL) is added into the solution of compound 12 (150mg, 0.3mmol) and in ring Mixture is stirred at a temperature of border 3 hours.Solvent is removed under reduced pressure, obtains thick amine salt, is directly used in following reaction.m/ z(ESI)435.8(M++H)。
Amine salt is suspended in CH2Cl2In (2mL), be cooled to 0 DEG C and addition phosgene (15% in toluene, 0.24mL, 0.36mmol), triethylamine (0.14mL, 1mmol) is then added.After 1 hour, it is concentrated under reduced pressure reaction solution.It will be remaining Object is dissolved in pyridine (3mL), addition DiTBS- gemcitabines (0.147g, 0.3mmol) and DMAP (0.19g, 1.5mmol). Reaction mixture stirred overnight at 70 DEG C, is concentrated under reduced pressure and residue is purified by flash chromatography on silica.By products therefrom It is dissolved in THF (2mL) and is cooled to 0 DEG C, addition TBAF (THF solution of 1M, 1mL, 1mmol).After 1 hour, decompression is dense Contracting reaction mixture and residue is purified by flash chromatography on silica, obtains compound 13.1H NMR(CDCl3)δ12.8(1H, br),7.96(1H,m),7.64-7.56(4H,m),7.48-7.3(4H,m),7.24-6.98(5H,m),6.02(1H,m),5.09 (2H,m),4.49(1H,m),4.1-3.85(3H,m),3.8-3.3(4H,m),3.2-2.8(6H,m),m/z(ESI)725.4(M+ +H)。
E.
At -10 DEG C, to (4- brombutyls) (ethyl) amine hydrobromate (0.4mmol, 104mg) and PCl3 (0.4mmol, 200 μ l) TEA (2.4mmol, 340 μ l) is slowly added in solution in DCM (5mL).Acquired solution 10 is stirred at room temperature to divide Clock.Suspension of a (0.4mmol, 130mg) in DCM (2mL) is added in the solution, and stir mixture at room temperature One hour.Solid b is added in reaction mixture and is stirred at room temperature one hour.By reactant be cooled to -10 DEG C and Add tert-butyl hydroperoxide (0.44mmol, the decane solution of 88 μ l, 5.5M).It is stirred at room temperature after 10 minutes, it will The reaction mixture is poured into the 5%HCl of cooling, is extracted with DCM.Organic layer is washed with brine, through MgSO4Dry, filtering is dense Contracting.Residue is purified with flash chromatography (hexane containing ethyl acetate, 0 to 100%), obtains product 1.At room temperature, to production Addition TFA (1ml) in solution (1mL) of the object 1 in DCM.Acquired solution is stirred 30 minutes.Remove solvent and residue is molten Solution is in ethyl acetate.Use 10%NaHCO3Wash ethyl acetate solution.Crude product with flash chromatography (MeOH/DCM, 0 to 10%) it purifies, obtains product TH 3057 (15mg).1H NMR(d4-MeOD,400MHz)δ8.01-8.00(dd,1H),7.75- 7.7(m,3H),7.61(d,2H),7.43(t,2H),7.36-7.29(dd,2H),7.18-7.14(m,4),6.2-6.1(m, 1H),6.0-5.9(dd,1H),5.1-5.01(m,2H),4.3-4.14(m,3H),4.1-4.0(m,1H),3.4-3.3(m,2H), 3.1-2.95 (m, 4H), 1.8-1.7 (m, 2H0,1.7-1.55 (m, 2H), and 1.1-1.3 (t, 3H).31P NMR(d4-MeOD, 161.9MHz) δ 11.93 (S) and 11.56 (S).19F NMR(d4-MeOD,376.3MHz)δ-77.35(S)。
The in vitro human tumor cell line cytotoxicity analysis of example 2.
The in vitro proliferation data of related H460 acellulars lung cancer human tumor cell line is based on by being exposed to The compound of various concentration 2 hours then carries out washing step and addition fresh culture, then makes growth and carry out cell Viability stain, and the IC measured compared with the reference material only with medium treatment50It measures.
In detail, by the positive cell for carrying out exponential growth with 4 × 103The density of a cells/well be inoculated in 96 porose discs and In 5%CO at 37 DEG C2, cultivate 24 hours in 95% air and 100% relative humidity, subsequent addition test compound.It will change Object is closed to be dissolved in 100%DMSO with final test concentration needed for 200 times.When adding drug, with complete medium by chemical combination Object is further diluted to ultimate density needed for 4 times.The aliquot of 50 μ l prescribed concentration compounds is added to and has contained 150 μ l In the microtiter well of culture medium, the final drug concentration reported is generated.After drug is added, 37 DEG C, 5%CO2, These disks are cultivated under 95% air and 100% relative humidity 72 hours.At the end of this is cultivated, alma indigo plant analytic approach is used (AlamarBlue assay) quantifies living cells.50% growth is caused to press down using Prism softwares (Irvine, CA) calculating Drug concentration (the IC of system50)。
Cell Proliferation be exist (3 micro-molar concentration) and there is no specific AKR 1C3 enzyme inhibitors in the case of into Row.It is carrying out compound before processing 2 hours, the example for being added to inhibitor is being added in cell culture.Inhibitor used For Flanagan et al., the compound in the 962-977 pages of Bioorganic and Medicinal Chemistry (2014) 36。
In the proliferation data in the presence/absence of specific AKR 1C3 inhibitor TH compounds in H460
This data confirms that mankind AKR 1C3 promote the activation of more than compound.
It should be understood that although by certain aspects, embodiment and optionally existing feature specifically discloses the present invention, Those skilled in the art can to these aspects, embodiment and optionally existing feature is modified, improves and changed, and these Modification, improvement and variation are considered within the scope of the present invention.
The generally and in general manner description present invention herein.The type of relatively narrower in the range of overall disclosure And subclass group respectively also forms the part of the present invention.In addition, in feature or aspect of the invention with marlcush group In the case that (Markush group) form is described, it would be recognized by those skilled in the art that the present invention is also therefore with the horse Any individual member in assorted group of library or member's subgroup form are described.

Claims (21)

1. a kind of compound with Formulas I,
Or its respective pharmaceutically acceptable salt or solvate, wherein
X10For O, S, SO or SO2；
A is C6-C10Aryl, 5 to 15 unit's heteroaryls or-N=CR1R2；
R1And R2It is each independently hydrogen, C1-C6Alkyl, C3-C8Cycloalkyl, C6-C10Aryl, 4 to 15 circle heterocyclic rings, 5 to 15 yuan it is miscellaneous Aryl, ether ,-CONR13R14Or-NR13COR14；
X, Y and Z is each independently hydrogen, CN, halogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C8Cycloalkyl, C6-C10 Aryl, 4 to 15 circle heterocyclic rings, 5 to 15 unit's heteroaryls, ether ,-CONR13R14Or-NR13COR14；
Each R independently is hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C8Cycloalkyl, C6-C10Aryl, 4 to 15 yuan Heterocycle, 5 to 15 unit's heteroaryls, ether ,-CONR13R14Or-NR13COR14；
R13And R14It is each independently hydrogen, C1-C6Alkyl, C3-C8Cycloalkyl, C6-C10Aryl, 4 to 15 circle heterocyclic rings, 5 to 15 yuan it is miscellaneous Aryl or ether；
Wherein L1And D is defined as follows：
L1It is selected from：
R40And R41It independently is hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C3-C8Cycloalkyl, C6-C10Aryl, 4 to 15 Circle heterocyclic ring or 5 to 15 unit's heteroaryls；
R42For optionally through 1 to 3 C1-C6Alkyl-substituted C2-C3It stretches alkyl or stretches miscellaneous alkyl；
V (-) is any anion, preferably pharmaceutically acceptable anion；
D is so that D-OH is the part of anticancer drug, and wherein OH is aliphatic hydroxide radical or phenolic hydroxyl group or is attached to be as provided herein To the OH parts of phosphorus atoms；Or
L1For：
R40As hereinbefore defined, R43Heterocycle is formed for hydrogen or together with D, and stretch phenyl moiety be optionally substituted and
D is so that D-NR43H is the part of anticancer drug；Or
L1For key ,-O-C (R40R41)2-、-O-C(R40R41)-NR40R41(+)-C(R40R41)-or
Wherein R40、R41And V as hereinbefore defined and
D is the anticancer drug containing three-level or two level nitrogen-atoms, wherein the three-level nitrogen-atoms or two level nitrogen-atoms are bonded to L1； And
Wherein described alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, ether group are optionally substituted.
2. compound as claimed in claim 1, with Formulas I-A：
Wherein remaining parameter is as defined in more than claim 1.
3. compound as claimed in claim 1, with formula 1A-1：
Wherein parameter is as defined in claim 1, and D is the cytotoxic agent HNR containing level-one amido or secondary amine43-D A part.
4. compound as claimed in claim 1, with formula 1A-2 or 1A-3：
The part that wherein parameter is as defined in claim 1 and D is the cytotoxic agent HO-D containing at least one hydroxyl.
5. compound as claimed in claim 1, with formula 1A-4,1A-6 or 1A-6-i：
Wherein parameter is as defined in claim 1, wherein in 1A-4, HO-D is the cytotoxicity containing at least one hydroxyl Agent, in 1A-6-I, DN40R41For drug, and in 1A-6, D is the drug containing two level nitrogen-atoms, wherein the two level nitrogen Atom is bonded to methylene, as shown above.
6. compound as claimed in claim 1, with formula 1A-5 or 1A-7：
Wherein, parameter is as defined in claim 1, in 1A-5, DN40R41For drug, in 1A-7, D is contains two level nitrogen The drug of atom, wherein the two level nitrogen-atoms is bonded to methylene, as shown above.
7. such as the compound of any one of claim 1 to 6, wherein Z is hydrogen.
8. such as the compound of any one of claim 1 to 7, wherein X is hydrogen.
9. such as the compound of any one of claim 1 to 8, wherein Y is hydrogen or halogen.
10. such as the compound of any one of claim 1 to 9, wherein A is the C being optionally substituted6-C10Aryl.
11. such as the compound of any one of claims 1 to 10, wherein A is the phenyl being optionally substituted.
12. such as the compound of any one of claim 1 to 9, wherein A is 5 to 15 unit's heteroaryls being optionally substituted.
13. such as claim 1 to 9 and any one of 12 compound, wherein A is the pyridyl group being optionally substituted.
14. such as the compound of any one of claim 1 to 9, wherein A is-N=CR1R2, wherein R1And R2As in claim 1 It is defined.
15. such as the compound of any one of claim 1 to 14, wherein each R is hydrogen.
16. such as the compound of any one of claim 1 to 14, wherein one of R group is hydrogen and another R group is C1-C6 Alkyl or wherein R group are non-hydrogen substituent as defined in claim 1.
17. such as claim 1 to 14 and any one of 16 compound, wherein R is methyl.
18. such as the compound of claims 1 or 2, wherein R40、R41And R43It is each independently hydrogen or methyl and R42For-CH2- CH2Or CH2-C(Me)2-。
19. a kind of pharmaceutically acceptable composition, it includes the compounds and at least of such as any one of claim 1 to 18 A kind of pharmaceutically acceptable excipient or supporting agent.
20. a kind of method for the treatment of cancer, it includes to patient's administration therapeutically effective amount in need such as claim 1 to 18 Any one of compound or the composition such as claim 19, thus treating cancer.
21. a kind of method for preparing the compound as claimed in claim 1 with Formulas I, it includes the compounds for making to have Formula II：
Wherein L is leaving group and remaining parameter is as defined in claim 1；With the compound with formula III：
Wherein X10As defined in claim 1；And optionally existing alkali contact, so as to provide the compound with Formulas I.
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